Coated bioabsorbable beads for wound treatment

ABSTRACT

The invention provides a material for use in a wound dressing or wound implant, the material comprising a plurality of beads, wherein each bead comprises a porous core of a first bioabsorbable material and a substantially non-porous layer of a second bioabsorbable material around the core. The porous core is preferably a sponge formed by freeze-drying a liquid suspension of the first bioabsorbable material. The preferred diameter of the beads is 0.1-4.0 mm, and the beads are preferably dispersed in a liquid or solid matrix. The invention also provides a method of making beads for use in the materials of the invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is based upon PCT Application Serial No.PCT/GB97/00638, filed Mar. 7, 1997, which claims priority from EuropeanPatent Application Serial No. 9605422.6, filed on Mar. 15, 1996.

The present invention relates to coated bioabsorbable beads for use in awound dressing or wound implant.

It is known to use collagen-based bioabsorbable beads for augmentingsoft tissue in wound dressings and wound implants. U.S Pat. No 4,837,285describes the use of collagen matrix beads, the beads being formed froma sponge of resorbable collagen. The beads have an average pore size offrom 50 to 350μm, with the collagen comprising from 1 to 30% by volumeof the beads. The size of the beads is preferably from 0.1 to 4 mmdiameter. The collagen matrix is sufficiently open to simulate cellularingrowth therethrough, and yet sufficiently stiff and non-compressibleto fill and protect a wound, and sufficiently moisture and gas permeableto prevent liquid pooling on a wound and to permit sufficient oxygendiffusion for promoting wound healing.

EP-A-0648480 describes wound implant materials comprising a plurality ofbioabsorbable microspheres bound together by a bioabsorbable matrix. Themicrospheres are preferably hollow microspheres or microcapsules boundtogether in a freeze-dried matrix. Preferably, at least 90% of themicrospheres have diameters between 0.2 and 1.0 mm. The use of closelypacked microspheres having controlled diameters is said to allow goodcontrol over the porosity of the implant material.

A need remains for improved materials for use in wound dressings andwound implants. Such a material should preferably be inexpensive andeasy to manufacture in a range of wound treatment formats. The materialshould preferably be fully bioabsorbable and non-antigenic. The materialshould preferably allow precise control of wound healing kinetics so asto assist rapid wound healing with minimum scarring.

It is an object of the present invention to provide a material for usein a wound dressing or wound implant having the desirable propertieslisted above.

It is a further object of the present invention to provide a method ofmaking bioabsorbable beads for use in a material for use in wounddressings or wound implants having the desirable properties listedabove.

The present invention provides a material for use in a wound dressing ora wound implant. The material comprises a plurality of beads, whereineach bead comprises a porous core of a first bioabsorbable material anda substantially non-porous layer of a second bioabsorbable materialaround said core.

The first and second bioabsorbable materials may be any materials thatare fully absorbable in the mammalian body. Such materials includesynthetic bioabsorbable materials commonly used for surgical sutures,implants and the like, for example absorbable polymers and copolymersmade from poly-glycolide, poly-lactide, ε-caprolactone, p-dioxanone,trimethylene carbonate and dimethyl trimethylene carbonate monomers.

Preferably, the first and second bioabsorbable materials are biopolymermaterials or chemically modified biopolymer materials. Such materialsinclude polysaccharides such as oxidised regenerated cellulose,alginates, chitosan or naturally occurring gums such as guar gum,xanthan gum or the like. Suitable biopolymers also includeglucosaminoglycans, such as hyaluronic acid, chondroitin sulphate,heparin and heparan sulphate. However, the preferred biopolymers arehyaluronic acid and its salts, and the structural proteins such ascollagen, fibrin, laminin or fibronectin. More preferred is collagen,which encompasses all collagen types including type I collagen, type IIcollagen, atelocollagen, pepsin-solubilised collagen and gelatin.Fibrous, insoluble collagen is most preferred.

Collagen is preferred because of its low antigenicity, readyavailability at moderate cost, and well-understood properties.

Preferably, the first bioabsorbable material consists essentially ofcollagen. More preferably, both the first and second bioabsorbablematerials consist essentially of collagen.

The porous core of the first bioabsorbable material is preferably abioabsorbable sponge, for example a product of freeze-drying(lyophilising) or solvent drying a frozen liquid dispersion of thebiopolymer. Such sponges generally have irregular, interconnected pores.Preferably, the average pore diameter is in the range of 50 μm to 350μm, which is thought to be the optimum size range for fibroblastingrowth.

Preferably, the beads are substantially spherical. More preferably, thesubstantially spherical beads comprise a substantially spherical porouscore enclosed in a substantially non-porous layer of substantiallyuniform thickness.

Preferably, the mean outside diameter of the beads in the range 0.1 to4.0 mm. More preferably, the mean outside diameter of said beads is inthe range 0.2 to 1.0 mm. Preferably, the layer of the secondbioabsorbable material is of substantially uniform thickness.Preferably, the average thickness of said layer is in the range 0.01 mmto 1.0 mm, more preferably 0.02 mm to 0.1 mm. Preferably, said layerforms a substantially continuous coating over the core to substantiallyprevent cellular invasion of the core until the layer has fully degradedin the body.

The beads may also comprise an active therapeutic agent in the porouscore and/or in the layer around the core. Preferred active therapeuticagents include growth factors such as TGFβ, platelet derived growthfactor (PDGF) or fibroblast growth factor (FGF) that can promote theingrowth of wound healing cells. The beads are especially suitable forachieving slow, more especially phased release of active therapeuticagents at the wound site. Such agents can include antiseptics such aschlorhexidine or silver sulphadiazine, antibiotics such as a penicillinsor a tetracyclins, steroids such as cortisone or prednisone, ornon-steroidal anti-inflammatory drugs such as Ibuprofen, naproxen oracetaminophen. Phased release of the active therapeutic agents can beachieved by having different concentrations of one or more differentactive agents in the porous core and the outer layer of the bead,respectively.

In certain preferred embodiments the material according to the presentinvention is a fluid, gel or paste comprising the coated beads asdescribed above dispersed in a pharmaceutically acceptable liquid or gelcarrier. The carrier can be a non-toxic base for forming an ointment,gel or injectable fluid incorporating the coated beads. The carrier ispreferably an aqueous carrier, and may also comprise a polyhydricalcohol such as propyleneglycol as a humectant, a pharmaceuticallyacceptable gelling agent such as gelatin, or hyaluronic acid and itssalts. The carrier may include pharmaceutical active agents, includingany one or more of the pharmaceutical active agents for the beadsenumerated above.

In other preferred embodiments the material according to the presentinvention may be a solid wound implant material comprising a pluralityof the coated beads bound together by a bioabsorbable matrix, asdescribed and claimed in our pending European patent applicationEP-A-0648480, the entire contents of which are expressly incorporatedherein by reference.

Preferably, the matrix is a solid bioabsorbable material, preferablyformed by freeze-drying an aqueous dispersion of a bioabsorbablematerial that has been used to bind the coated beads.

Preferably, the coated beads make up at least 30%, more preferably atleast 40%, and most preferably at least 50% of the volume of thematerial according to the present invention.

The present invention also provides a method of making bioabsorbablebeads for use in wound dressings or implants, the method comprising:providing a dispersion of a first bioabsorbable material in a liquidsolvent; generating droplets of the dispersion; freezing the droplets toform frozen droplets; freeze-drying or solvent drying the frozendroplets to form discrete porous cores of said first bioabsorbablematerial; and coating the porous cores with a substantially non-porouslayer of a second bioabsorbable material.

The preferred compositions and dimensions of the bioabsorbable beads areas described above for the materials according to the present invention.

Preferably, the liquid solvent is an aqueous solvent. The dispersion maybe a suspension or a solution, and preferably has a weight concentrationof 0.01-5% w/v, more preferably 0.02%-2% w/v.

The droplets of the dispersion can be generated by methodsconventionally known in the art, including spraying the dispersionthrough a suitable nozzle with or without application of an electricfield, pulsing individual droplets from a capillary, or emulsifying theaqueous dispersion in a water-immiscible solvent such as a volatilehydrocarbon.

Once formed, the droplets are preferably immediately frozen, for exampleby spraying the droplets into liquid nitrogen. Emmulsified droplets arefrozen by chilling the emulsion to a temperature below the freezingpoint of the dispersion but above the freezing point of thewater-immiscible solvent, followed by filtering off the frozen droplets.The frozen droplets are then preferably sieved to isolate dropletshaving the desired size range. Broadly speaking, the porous cores formedby freeze-drying or solvent drying the frozen droplets will haveapproximately the same dimensions as the frozen droplets.

The frozen droplets are then freeze-dried or solvent dried. Thefreeze-drying is preferably carried out over a temperature range of −20°C. to ambient using conventional freeze-drying apparatus. The solventdrying is preferably carried out as described in U.S. Pat No. 3,157,524,the entire contents of which are expressly incorporated herein byreference. Briefly, the solvent drying is carried out by immersing thefrozen droplets in a series of anhydrous isopropanol baths maintained atambient temperature, followed by evaporation of residual isopropanolunder vacuum.

Finally, the porous cores of bioabsorbable material formed in the aboveprocess steps are coated with a substantially non-porous layer of asecond bioabsorbable second material. The coating is preferably carriedby dipping the cores in a solution of the second bioabsorbable material,or by spray coating, followed by drying. The thickness of the coatinglayer will depend on the concentration and viscosity of the dippingsolution, and on the number of dipping/spray coating operations carriedout.

The finished coated beads, preferably comprise less than 10% water byweight, and are preferably then sterilized by gamma irradiation.

The coated beads having porous bioabsorbable cores obtained by themethod of the present invention are especially useful for soft tissuefilling in wound dressings and implants. This is because the intersticesbetween the beads in the wound dressing or implant are rapidly invadedby wound healing cells, especially fibroblasts. However, the interiorsof the beads themselves are not invaded until after the non-porouscoating on the beads has been degraded by bioabsorbtion. This allowsmore accurate control over later stage wound healing, and hence permitsreduction in scarring.

Specific embodiments of the present invention will now be describedfurther, by way of example, with reference to the accompanying Figures,in which:

FIG. 1 shows a photomicrograph of part of a section through a coatedbead obtained by the method of the present invention;

FIG. 2 shows a detail of part of the bead of FIG. 1 at highermagnification;

FIG. 3 shows a photomicrograph of a section through a bead obtained by amethod according to the present invention, but having a thicker coatinglayer than the bead of FIGS. 1 and 2;

FIGS. 4 and 5 show a photomicrographs of sections through beads thathave been implanted in rats.

EXAMPLE 1 Preparation of Coated Beads

Coated beads for use in materials according to the present invention areprepared by a method according to the present invention, as follows. Asolution of 1% chitosan in 1% acetic acid is pumped through a finepipette tip using a peristaltic pump. The droplets thus formed aredropped into liquid nitrogen in a Dewar flask to form frozen droplets ofthe solution. The Dewar flask is shaken slight to ensure that the beadsdo not stick together before they are completely frozen. The frozenbeads are collected and sieved to collect beads having diameters in therange 1 mm-2 mm.

The frozen droplets are then transferred to a freeze-dryer andlyophilized at −20° C. to about +20°. The freeze-dried beads are thencoated by dipping them into a 10-20% w/v solution of a 1:1 polylacticacid/polyglycolic acid copolymer having molecular weight 50,000-75,000(Sigma Chemical Co.) in chloroform at ambient temperature for about 10seconds, followed by drying in a current of warm air.

The resulting beads are sectioned and the scanning electron micrographsshown in FIGS. 1-3 are obtained. The micrographs show the porous, spongestructure of the freeze-dried core and the substantially non-porousnature of the coating over the core. It can be seen that the core hasflattened pores with typical dimensions of 100 μm×100 μm×30 μm. Thethickness of the non-porous coating on the beads is about 30 μm.

EXAMPLE 2 Use of the Coated Beads as a Wound Implant

Beads produced as above are sterilised by gamma irradiation andimplanted into 1×1 cm subcutaneous pockets made in the backs of rats.After 7 and 14 days the rats are sacrificed and the implanted materialstabilised by placing in formalin solution. 7 μm sections are cut andstained with Massons Trichrome stain to obtain the photomicrographs ofFIGS. 4 and 5. These show fibroblasts surrounding the beads, and newcollagen and blood vessels are visible in the spaces between the beads.

The above embodiments have been described by way of example only. Manyother embodiments of the present invention falling within the scope ofthe accompanying claims will be apparent to the skilled reader.

What is claimed is:
 1. A material for use in a wound dressing or a woundimplant, the material comprising a plurality of beads, wherein each beadcomprises a porous core of a first bioabsorbable material and asubstantially non-porous layer of a second bioabsorbable material aroundsaid core.
 2. A material according to claim 1, wherein the first and/orthe second bioabsorbable material consists essentially of collagen.
 3. Amaterial according to claim 1 or 2, wherein said beads are substantiallyspherical.
 4. A material according to claim 1 or 2, wherein the meanoutside diameter of said beads is in the range 0.1 to 4.0 mm.
 5. Amaterial according claim 4, wherein the mean thickness of said layer ofsaid second bioabsorbable material is in the range 0.01 mm to 1.0 mm. 6.A material according to claim 5, wherein the mean pore diameter in saidporous core is in the range 50 μm to 350 μm.
 7. A material according toclaim 6, further comprising an active therapeutic agent in said porouscore and/or in said substantially non-porous layer.
 8. A materialaccording to claim 7, wherein said material is a fluid or pastecomprising said beads dispersed in a liquid or gel carrier.
 9. A methodof making bioabsorbable beads for use in wound dressings or implants,the method comprising: providing a dispersion of a first bioabsorbablematerial in a liquid solvent; generating droplets of said dispersion;freezing said droplets to form frozen droplets; freeze-drying orsolvent-drying the frozen droplets to form discrete porous cores of saidfirst bioabsorbable material; and coating said porous cores with asubstantially non-porous layer of a second bioabsorbable material.
 10. Amethod according to claim 9, wherein said solvent is an aqueous solvent.